Although the cause of Parkinson~s disease (PD) is unknown, both environmental and genetic factors are likely to contribute to the degenerative process underlying the disease. Results of epidemiological studies suggest an association between an increased risk for PD and ex posure to chemicals present in the rural environment, raising the possibility that pesticides may play a role in PD neurodegeneration. The aim of this proposal is to screen a selected number of agricultural chemicals in terms of their specific effects on dopaminergic terminals in the striatum and dopaminergic cell bodies in the substantia nigra. In particular, bipyridyl (paraquat, PQ, diquat, DQ) chlorophenoxy (2,4-dichlorophenoxyacetic acid, 2,4-D), organochlorine (dieldrin), roteniod (rotenone) and thiocarbamate (diethyldithiocarbamate, DDC) chemicals were chosen based on existing epidemiological, clinical and experimental clues. Experiments are designed to determine whether or not any of these compounds are capable of causing changes in dopamine levels and metabolism in the mouse striatum and/or substantia nigra. Chemical interactions will also be evaluated by combined treatments. Finally, the hypothesis that the neurotoxic properties of PQ, DQ, 2,4-D, dieldrin, rotenone and/or DDC are promoted or enhanced in animals pre-lesioned with a selective dopaminergic toxicant will be tested by injecting these compounds after 1 -methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Results of these preliminary experiments will provide much needed experimental evidence in favor of or against a role of agricultural chemicals in the pathogenesis of PD. A positive correlation between the pesticide compounds tested and dopamine changes will constitute the basis for developing mechanistically-oriented research as well as targeted epidemiological studies.